Novel Pyrazolo[1,5-a]pyrimidines as Translocator Protein 18 kDa (TSPO) Ligands: Synthesis, in Vitro Biological Evaluation, [F-18]-Labeling, and in Vivo Neuroinflammation PET Images

作者：Damont Annelaure^*; Medran Navarrete Vincent; Cacheux Fanny; Kuhnast Bertrand; Pottier Geraldine; Bemards Nicholas; Marguet Frank; Puech Frederic; Boisgard Raphael; Dolle Frederic

来源：Journal of Medicinal Chemistry, 2015, 58(18): 7449-7464.

DOI：10.1021/acs.jmedchem.5b00932

A series of novel pyrazolo[1,5-a]pyrimidines, closely related to N,N-diethyl-2-(2-(4-(2-fluoroethoxy)-phenyl)-5,7-dimethylpyrazolo[1,5-a]pyrimidin-3-yl)acetamide (2, DPA-714), were synthesized and biologically in vitro evaluated for their potential to bind the translocator protein 18 kDa (TSPO), a protein today recognized as an early biomarker of neuroinflammatory processes. This series is composed of fluoroalkyl- and fluoroalkynyl- analogues, prepared from a common iodinated intermediate via Sonogashira coupling reactions. All derivatives displayed subnanomolar affinity for the TSPO (0.37 to 0.86 nM), comparable to that of 2 (0.91 nM). Two of them were radiolabeled with fluorine-18, and their biodistribution was investigated by in vitro autoradiography and positron emission tomography (PET) imaging on a rodent model of neuroinflammation. Brain uptake and local accumulation of both compounds in the AMPA-mediated lesion confirm their potential as in vivo PET-radiotracers. In particular, [F-18]23 exhibited a significantly higher ipsi- to contralateral ratio at 60 min than the parent molecule [F-18]2 in vivo.

• 出版日期2015-9-24
• 单位中国地震局